Process for the Preparation of Aclidinium Bromide

ABSTRACT

A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) comprises reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents selected from the group of amides and/or the group of solvents with a sulfoxide group. Also provided is a crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ. A pharmaceutical composition comprises aclidinium bromide according to the invention and a pharmaceutically acceptable excipient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of and claims priority to U.S. patentapplication Ser. No. 15/562,814 filed Sep. 28, 2017, published as U.S.Patent Application Publication US 2018-0105517 A1, which is a filingunder 35 U.S.C. 371 of International Application No. PCT/GB2016/050888filed Mar. 30, 2016, entitled “Process for the Preparation of AclidiniumBromide” which claims priority to Portuguese Patent Application No.108370 filed Mar. 30, 2015, which applications are incorporated byreference herein in their entirety.

FIELD OF INVENTION

The present invention relates to a process for the preparation ofaclidinium salts, particularly aclidinium bromide. The invention alsoconcerns a pharmaceutical composition comprising aclidinium in the formof a dry powder, solution or suspension.

BACKGROUND OF THE INVENTION

The present invention relates to a novel process for the preparation ofaclidinium salts. The chemical name of aclidinium is(3R)-3-[2-hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane.The structure of the aclidinium salts is depicted below (I).

wherein:X⁻ is a pharmaceutically acceptable anion, such as bromide, chloride oriodide.

The preferred salt is aclidinium bromide, a quaternary ammonium salt.

Aclidinium bromide is a white to off-white crystalline powder. Theactive form is the R-isomer and the S-isomer has small affinity formuscarinic receptors in vitro and limited effect on acetylcholineinduced bronchoconstriction. The drug is formulated as an inhalationpowder, comprised of a mixture of micronized aclidinium bromide andα-lactose monohydrate.

Aclidinium bromide is a muscarinic antagonist and is availablecommercially as Bretaris Genuair (EU Members States), Tudorza Pressair(US and Canada) and Eklira Genuair (UK).

This compound as well as a process for its manufacture is described inWO 01/04118. Later, an improved process was described in WO2008/009397and also presented in the article J. Med. Chem. 2θ09, 52, 5076-5092.

The process of aclidinium bromide described in WO 01/04118 has two maindisadvantages:

-   -   The use of a potential genotoxic reagent—3-phenoxy propyl        bromide with a large excess—5 equivalents    -   A long reaction time—72 hours.

The process described in WO2008/009397 aims at overcoming thesedisadvantages by using specific groups of solvents, reducing the amountof 3-phenoxypropyl bromide and controlling the content of this reagentin the final product.

This process is able to reduce the reaction time to 8 hours, using aspecific solvent (ketones or cyclic ethers having a boiling pointbetween 50° C. and 210° C.) while using a reduced amount of the reagent3-phenoxypropyl bromide. However this comes at the cost of performingthe reaction under reflux.

Moreover, taking into account that the solvents considered have boilingpoints from 50° C. and 210° C., the reaction temperature, in some cases,must be extremely high, which brings extra operational challenges to theprocess.

SUMMARY OF INVENTION

We have now devised a process which consistently affords product withhigh chemical purity, higher than 99.0% preferably over 99.5%, and aconsistent polymorphic form, whilst minimizing or eliminating thedisadvantages referred to above. The present process also enables themanufacture of a product with controlled particle size.

According to one aspect of the present invention, there is provided aprocess for preparing(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (aclidinium bromide) by reacting2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) ylmethyl ester and 3-phenoxypropyl bromide, wherein the reaction takesplace in a solvent or mixture of solvents that are selected from thegroup of amides and/or the group of solvents with a sulfoxide group.

In another aspect, the present invention provides a crystallineaclidinium bromide characterized by a powder XRPD pattern having peaksat 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ,20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ,29.2±0.2° 2θ, 30.8±0.2° 2θ.

In another aspect, the present invention provides a mixture ofcrystalline and amorphous aclidinium bromide, optionally obtainableaccording to the process described herein, characterized by a powderXRPD pattern as depicted in FIG. 9.

In another aspect, the present invention provides a process of preparingaclidinium bromide, which process comprises drying a solution ofaclidinium bromide in a solvent or a mixture of solvents, preferably byspray drying.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable salt of aclidinium,preferably aclidinium bromide, as disclosed herein and apharmaceutically acceptable excipient. Preferably, the aclidiniumbromide is made according to the process described herein.

In another aspect, the present invention provides aclidinium bromide asdisclosed herein, or aclidinium bromide obtained according to theprocess as disclosed herein; or a pharmaceutical composition comprisingaclidinium bromide as disclosed herein for use in medicine, preferablyfor use in treating chronic obstructive pulmonary disease (COPD).

The preparation of aclidinium bromide involves a transesterificationreaction between 3R—quinucidinol (II) and MDTG (III) to produceN-despropylaclidinium (IV), followed by the reaction ofN-despropylaclidinium with 3-phenoxypropyl bromide (V) (quaternizationreaction) to synthetize aclidinium bromide (Scheme 1).

For the transesterification reaction a variety of bases can be used,among others: K₂CO₃, sodium methoxide, sodium ethoxide, sodium tertbutoxide, triazabicyclodecene (TBD) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

By using a different solvent or a mixture of solvents in thequaternization reaction, the process of the present invention is able toovercome the disadvantages of the prior art while carrying out thereaction at a temperature below 100° C., namely at temperatures aroundroom temperature, most preferably at temperatures from 20 to 30° C.,preferably at a temperature around 30° C. or 20° C.

Surprisingly, the reaction time is maintained at less than 8 hours,preferably less than 6 hours, more preferably less than 4 hours, and theamount of genotoxic reagent used is preferably maintained in the rangeof 1.2 to 2.0 mole equivalents.

The solvent chosen can be a solvent with a sulfoxide group, preferablydimethylsulfoxide (DMSO), diethylsulfoxide, or any of the solvents ofthe amide group, preferably dimethylformamide (DMF), (dimethylacetamide)DMA, or mixtures thereof.

A further advantage of the quaternization reaction described is that thesolid material thus obtained can be micronized to achieve the desiredparticle size range, for example a particle size distribution suitablefor inhalation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1—depicts the powder XRPD pattern of an anhydrous crystalline formof aclidinium bromide.

FIG. 2—depicts the Scanning Electron Microscopy (SEM) of the productwith particles presenting plate like shape particles.

FIG. 3—depicts the Scanning Electron Microscopy (SEM) of the productwith particles presenting cube-shape particles.

FIG. 4—depicts the Scanning Electron Microscopy (SEM) of the productwith particles presenting very small parallel piped shape particles.

FIG. 5—depicts the Thermal Gravimetric Analysis of anhydrous aclidiniumbromide.

FIG. 6—depicts a Differential Scanning calorimetry (DSC) of anhydrousaclidinium bromide.

FIG. 7—depicts a XRPD pattern of a mixture of crystalline form andamorphous aclidinium bromide obtained by spray drying process.

FIG. 8—depicts the Scanning Electron Microscopy (SEM) of the productafter micronization.

FIG. 9—depicts a powder XRPD pattern of a mixture of crystalline andamorphous aclidinimum bromide.

DETAILED DESCRIPTION OF THE INVENTION

This invention concerns a process for preparing(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide by reacting (3R)-1-azabicyclo[2.2.2]oct-3-ylhydroxy(di-2-thienyl)acetate and 3-phenoxypropyl bromide, wherein thereaction takes place in a solvent or mixture of solvents that areselected from the group of amides and/or other solvents or mixture ofsolvents with a sulfoxide group at a temperature below their boilingpoint. The reaction temperature is below 100° C., preferably below 50°C., and in preferred aspects the reaction temperature is from about 30°C. to about 2θ° C., suitably about 30° C., or about 20° C.

In a preferred aspect, the reaction takes place under a flow of an inertgas, suitably a dry inert gas, preferably under a flow of dry nitrogen,dry helium or a mixture thereof.

In a preferred aspect, the reaction takes place at a pressure below theatmospheric pressure. Standard atmospheric pressure is 101325 Pa(equivalent to 760 mmHg), and preferably the pressure is below this.Alternatively, the pressure may be below the ambient atmosphericpressure, based on the location where the reaction is taking place.

Preferably, any alcohol formed during the reaction is removed from thereaction mixture.

Preferably, the reaction solvent is DMF or is a mixture of solventscontaining DMF, DMA or a mixture of solvents containing DMA, DMSO or amixture of solvents containing DMSO. One preferred solvent is DMSO or amixture of solvents containing DMSO.

For example, when using DMSO as solvent the purity achieved is above99.5% without the need for any crystallization step. For other solventsa crystallization step may be needed in order to achieve the desiredpurity.

In a preferred aspect, the process of the invention is such that theequivalent mole ratio of 3-phenoxypropyl bromide to(3R)-1-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate is in therange of from 1.2 to 2.0, preferably from 1.5 to 2.0, more preferablyabout 1.8.

The content of the genotoxic impurity 3-phenoxypropyl bromide in thefinal product is always below 500 ppm, more preferably below 200 ppm.

The process of the invention preferably has a total reaction time is notmore than 8 hours. In a preferred aspect, the reaction time is not morethan 6 hours, more preferably not more than 4 hours.

The process of the invention may if desired further comprise the step ofpurification of aclinidium bromide by dissolving the product in DMSO (oranother suitable solvent) and using acetonitrile (or another suitablesolvent) as co-solvent to precipitate the purified product.

In a preferred process according to the invention, the aclidiniumbromide obtained is crystalline.

In one preferred aspect of the process according to the invention, theaclidinium bromide obtained is a mixture of crystalline and amorphousmaterial.

In a preferred aspect of the invention, an anhydrous crystalline form ofaclidinium bromide is obtained. This form is characterized by the powderXRPD pattern depicted in the FIG. 1 and having characteristicdiffraction peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2°2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2°2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ.

This anhydrous crystalline form can be obtained with different crystalhabits and morphologies.

This crystalline form of aclidinium bromide is preferably furthercharacterized by no weight loss by TGA, and also preferably furthercharacterized by a DSC thermogram having an endotherm peak at 228° C.

In one aspect, the crystalline form of aclidinium bromide provided maycomprise a minor amount of amorphous aclidinium bromide. Suitably, theamount is less than 2θ% by weight, preferably less than 10% by weight,more preferably less than 5% by weight (% by weight being expressed withrespect to the total amount of material).

Different morphology was observed when anti-solvent crystallizationtechnique was conducted. The particles exhibited a plate like shape byElectro Scanning Microscopy (SEM) analysis as shown in FIG. 2.

When a thermocycling process is used to crystallize the product,cube-shape particles are obtained, as shown in FIG. 3.

And when crystallization is carried out by cooling the reaction mixture,the product morphology consists of very small parallel piped shapeparticles, as shown in FIG. 4.

Anhydrous crystalline aclidinium bromide obtained according to theprocess described herein is further characterized by no weight lossuntil melting and decomposition by Thermal Gravimetric Analysis (TGA)FIG. 5.

Anhydrous crystalline aclidinium bromide is further characterized by aDifferential Scanning calorimetry (DSC) thermogram—FIG. 6—having asingle endothermic transition, at a temperature given by the onset ofthe transition (Tonset) of 227° C. This transition corresponds to themelting of the crystalline form.

The invention also concerns a process to obtain aclidinium salts,preferably aclidinium bromide, by drying a solution of the aclidiniumsalt in a solvent or in a mixture of solvents by lyophilization or spraydrying or by another suitable drying method. Preferably the drying stepis a spray drying step.

In one preferred aspect, said solvent or a mixture of solvents areselected from solvents with a sulfoxide group. Preferably the saidmixture contains DMSO and most preferably the solvent is DMSO.

In a preferred aspect, when the drying step is a spray drying process,the product obtained can either be crystalline, crystalline with a minorcontent of amorphous product, pure amorphous, amorphous with a minorcontent of a crystalline form or a mixture of amorphous and crystallineforms in different ratios.

The XRPD pattern (FIG. 7) depicts a mixture of a crystalline form andamorphous aclidinium bromide obtained by a spray drying process.

The invention also concerns a pharmaceutical composition comprisingaclidinium, preferably in the form of a dry powder, solution orsuspension of a pharmaceutical acceptable salt, which can for example beanhydrous, a hydrate or a solvate as described above in admixture with apharmaceutical excipient, preferably an acceptable dry powder carrier.

Preferably, the pharmaceutical acceptable salt form is aclidiniumbromide.

Suitably, the pharmaceutical acceptable carrier is lactose or α-lactosemonohydrate.

The invention also provides a pharmaceutical composition as describedherein for inhalation comprising aclidinium in the form of a dry powder,solution or suspension of a pharmaceutically acceptable salt asdescribed in herein or as obtained by a process as described herein,together with a pharmaceutically acceptable excipient.

Preferably, the pharmaceutical composition is in the form of a drypowder formulation where the pharmaceutically acceptable excipient is anacceptable dry powder carrier. The pharmaceutically acceptable carrieris preferably lactose or α-lactose monohydrate.

The invention can encompass a pharmaceutical composition as describedherein wherein aclidinium bromide is replaced with an alternativepharmaceutically acceptable salt form of aclidinium. However, the saltform used is preferably aclidinium bromide.

For example, the chloride or the iodide salts may be used. The syntheticroute for these salts is essentially identical to the process for makingthe bromide salt, except that a suitable chloride or iodide reagentshould be used. For example, 3-phenoxypropyl chloride may be usedinstead of 3-phenoxypropyl bromide.

EXAMPLES

This invention is illustrated by the following examples. These examplesare provided to illustrate particular aspects of the disclosure and donot limit the scope of the present invention.

HPLC analysis of the products of the following examples was conducted ona Zorbaz SB—C3 column (150 mm×3.0 mm×3.5 μm).

The mobile phase at a flow of 1.2 ml/min was a binary system of water(containing sodium methanesulfonate and potassium dihydrogenphosphate atpH3.0—Phase A) and a mixture of methanol:acetonitrile:phase A (10:40:50v/v/v). The total run time was 50 minutes.

Example 1—Transesterification Reaction Synthesis of(3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (CompoundIV)

To a solution of (3R)-quinuclidinol (10.30 g, 81.0 mmol) in 500 ml oftoluene was added methyl di(2-thienyl) glycolate (MDTG) (20 g, 78 mmol).The solution was refluxed with continuous distillation of toluene andreplacement with fresh toluene.

After distillation was added sodium methoxide (1.70 g, 31 mmol) anddistillation was carried out at 80°/90° C. under a flow of nitrogen,until the reaction is considered complete. The reaction is consideredcomplete when MDTG content is ≤2.0% in area by HPLC.

The reaction mixture is washed with water and with brine until thecontent of the impurity 2-hydroxy-2,2-bis(2-thienyl) acetic acid (DTG)was ≤1.5%.

The organic solution is concentrated under vacuum at a temperature equalto, or lower than, 50° C. until a final volume of 50 ml.

The suspension was cooled to 20°/25° C. and stirred at this temperatureover, at least, 2 hours.

The suspension was cooled to a temperature between 10° C. and 15° C. andstirred at this temperature over, at least, 4 hours.

The product was filtered and washed with isopropyl ether previouslycooled to a temperature between 10° C. and 15° C.

The desired product (18.4 g) was obtained with a purity of, not lessthan 99.2θ% in area, by HPLC.

Example 2—Transesterification Reaction Synthesis of(3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (CompoundIV)

A solution of (3R)-quinuclidinol (5.15 g, 40.5 mmol) in 250 ml oftoluene is heated until a temperature between 65° C. and 70° C. andsodium methoxide (0.65 g, 11.8 mmol) was added.

Under a flow of nitrogen at a temperature between 75° C. and 85° C. asolution of MDTG (10.0 g; 39.3 mmol) in 100 ml of toluene was addedduring around 1 hour.

Under a flow of nitrogen and at a temperature between 75° C. and 85° C.the azeotrope of toluene and methanol was removed by distillation (withreplacement of fresh toluene) until the reaction is considered complete.

The reaction mixture is washed with a 20% aqueous solution of NaCl fourtimes, until the content of DTG by-product in organic phase was ≤1.5%.

The organic phase was dried and concentrated under vacuum at atemperature equal to, or lower than 40° C. until a final volume of 25ml.

The suspension was cooled to 10°/15° C. and stirred at this temperature,at least, 5 hours.

The desired product (8.5 g) was obtained with a purity of, not less than98.0% by HPLC

Example 3—Quaternization Reaction Synthesis of aclidiniumbromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (Compound I)

In an inert atmosphere, to a suspension of(3R)-Azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (5 g; 14.26mmol) in 30 ml of DMF, 3-phenoxypropyl bromide (3.42 ml, 21.68 mmol) wasadded slowly at a temperature between 2θ° C. and 25° C.

The suspension was stirred at about 30° C. until the content of thestarting material content is below 0.5% in area by HPLC.

When the reaction was completed acetonitrile (43 ml) was added to thesuspension. The suspension was cooled at a temperature between 20° C.and 25° C. and stirred over 2 hours while maintaining the temperaturebetween 20° C. and 25° C.

The product was filtered and washed with acetonitrile, previously cooledto a temperature between 10° C. and 15° C.

Aclidinium bromide was obtained (7.48 g) with a purity of 99.4% in areaby HPLC.

Examples 4 to 8—Quaternization Reaction

In examples 4 to 8, the process followed was the process described inexample 3 where different quantities of the reaction solvent and of thereagent 3-phenoxypropyl bromide were used.

Equivalents Amount of 3- of Reaction phenoxypropyl solvent temperatureReaction Yield Ex: bromide Solvent ml/g (° C.) time (h) (%) 4 1.88 DMF8.6 30 91 5 1.88 DMF 3.7 30 3.5 90.8 6 1.16 DMF 3.7 30 6.5 90.6 7 1.52DMF 6.15 30 88.8 8 1.52 DMF 6.15 20 7 92.2

Using DMF as solvent the selected parameters were: 1,88 eq of3-phenoxypropyl bromide; amount of solvent 3.7 ml/g; temperature 30° C.

Example 9—Quaternization Reaction Synthesis of aclidiniumbromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (compound I)

In an inert atmosphere, to a suspension of(3R)-Azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (5 g, 14.26mmol) in 30 ml of DMA, 3-phenoxypropyl bromide (4.23 ml, 26.82 mmol) wasadded slowly at a temperature between 20° C. and 25° C.

The suspension was stirred at 30° C. until the content of the startingmaterial content is below 0.5% in area by HPLC.

When the reaction was completed, acetonitrile (43 ml) was added to thesuspension. The suspension was cooled at a temperature between 20° C.and 25° C. and stirred over 2 hours while maintaining the temperaturebetween 20° C. and 25° C.

The product was filtered and washed with acetonitrile, previously cooledto a temperature between 10° C. and 15° C.

Aclidinium bromide is obtained (7.4 g) with a purity of 98.98% in areaby HPLC.

Example 10—Quaternization Reaction Synthesis of aclidiniumbromide-(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (compound I)

In an inert atmosphere, to a suspension of(3R)-azabicyclo[2.2.2]oct-3-yl hydroxy(di-2-thienyl)acetate (4.50 g,12.84 mmol) in 27.7 ml of DMSO, 3-phenoxypropyl bromide (3.80 ml, 24.14mmol) was added at a temperature of about 30° C.

The suspension was stirred at 30° C. until the content of the startingmaterial content is below 0.5% in area by HPLC.

When the reaction is completed, acetonitrile (54 ml) was added to thesuspension; the suspension was cooled at a temperature between 20° C.and 25° C. and stirred over 2 hours while maintaining the temperaturebetween 20° C. and 25° C.

The product was filtered and washed with acetonitrile previously cooledto a temperature between 10° C. and 15° C.

Aclidinium bromide was obtained (5.8 g) with a purity of 99.88% in areaby HPLC.

Example 11—Purification of Compound (I) Purification of aclidiniumbromide-(3R)-3-[2-hydroxyl(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (Compound I)

In an inert atmosphere,(3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide (50 g) was added to 500 ml of dimethylsulfoxide at a temperaturebetween 40° C. and 45° C. To the solution obtained, 11 of acetonitrilewas added slowly.

The product crystallized and a slowly cooling was done until atemperature between 20° C. and 25° C.

The suspension was stirred over 2 hours while maintaining thetemperature between 20° C. and 25° C.

Aclidinium bromide purified was obtained (33 g) and with a purity of99.91% in area by HPLC.

Example 12—Micronization

Micronization was conducted by jet milling in order to conclude if theparticle size distribution (PSD) of the aclidinium bromide could beeasily adjusted to a range suitable for inhalation (1-5 μm). A 1.5″ jetmiller (Fluid Jet Mill J20/DS20) was used for the micronization fed withpure nitrogen. In this example the powder was added at constant flowrate by a double-screw type feeder, with Venturi and nozzles pressurebetween 4 to 10 bar.

The analytical results obtained are summarized in the table below. Theproduct obtained had a PSD within the inhalable range with a purityhigher than 99.5% and high yield (90% wt.). With only one passage thepowder reached the desirable PSD, and no presence of amorphous materialcould be detected on the product. In addition the SEM image of themicronized material revealed a homogeneous PSD (FIG. 8).

Batch Dv10; Dv50; Dv90 HPLC purity (area) Starting raw material 6.1;15.5; 35.9 99.9% Product after 1 cycle 1.3; 2.4; 4.6 99.7% Batch 1Product after 1 cycle 1.5; 2.6; 4.8 99.5% Batch 2

Measuring Conditions

All XRPD were obtained using high throughput XRPD set-up. Datacollection was carried out at room temperature using monochromaticCuK_(α) radiation in the 2θ region between 1.5° and 41.5°.

TGA/DSC

The instrument used was TGA/SDRA 851e (Mettler-Toledo) that wascalibrated for temperature with In and Al. The seals were pin holed andthe crucible heated in the TGA from 25° C. to 300° C., at a heating rateof 10° C./min

SEM

The instrument used was a Phillips SEM 525 microscope equipped with anexternal SE detector.

What is claimed is:
 1. A crystalline aclidinium bromide characterized bya powder XRPD pattern having peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ,13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ,24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ,characterized by no weight loss by TGA.
 2. Aclidinium bromide accordingto claim 1, further characterized by a DSC thermogram having anendotherm peak at 228° C.
 3. A mixture of crystalline and amorphousaclidinium bromide, characterized by a powder XRPD pattern as depictedin FIG.
 9. 4. A mixture of crystalline and amorphous aclidinium bromideaccording to claim 3 wherein 20 wt % or less, as a percentage of thetotal weight of material, of amorphous aclidinium bromide is present. 5.A pharmaceutical composition comprising aclidinium bromide according toclaim 1 and a pharmaceutically acceptable excipient.
 6. A pharmaceuticalcomposition comprising a mixture of crystalline and amorphous aclidiniumbromide according to claim 3 and a pharmaceutically acceptableexcipient.
 7. A pharmaceutical composition according to claim 5 forinhalation in the form of a dry powder, solution or suspension.
 8. Apharmaceutical composition according to claim 5 in the form of a drypowder formulation where the pharmaceutically acceptable excipient is anacceptable dry powder carrier.
 9. A pharmaceutical composition accordingto claim 8 wherein the pharmaceutically acceptable carrier is lactose orα-lactose monohydrate.
 10. A method comprising utilizing aclidiniumbromide according to claim 1 in medicine.
 11. A method comprisingutilizing a mixture of crystalline and amorphous aclidinium bromideaccording to claim 3 in medicine.
 12. A pharmaceutical compositionaccording to claim 6 for inhalation in the form of a dry powder,solution or suspension.
 13. A pharmaceutical composition according toclaim 6 in the form of a dry powder formulation where thepharmaceutically acceptable excipient is an acceptable dry powdercarrier.
 14. A method comprising utilizing pharmaceutical compositionaccording to claim 5 in medicine.
 15. A method comprising utilizingpharmaceutical composition according to claim 6 in medicine.
 16. Amixture of crystalline and amorphous aclidinium bromide according toclaim 3 wherein 10 wt % or less, as a percentage of the total weight ofmaterial, of amorphous aclidinium bromide is present.
 17. A method oftreating chronic obstructive pulmonary disease (COPD) comprisingadministering to a subject in need thereof the aclidinium bromideaccording to claim
 1. 18. A method of treating chronic obstructivepulmonary disease (COPD) comprising administering to a subject in needthereof the pharmaceutical composition of claim
 5. 19. A method oftreating chronic obstructive pulmonary disease (COPD) comprisingadministering to a subject in need thereof a mixture of crystalline andamorphous aclidinium bromide according to claim
 3. 20. A method oftreating chronic obstructive pulmonary disease (COPD) comprisingadministering to a subject in need thereof the pharmaceuticalcomposition according to claim 6.